One of the great challenges in medicine is finding more effective forms of treatment for a large number of life-threatening, but curable diseases, such as cancer. One of the challenges to be overcome relates to the inadequacies surrounding the ability to administer therapeutic agents, imaging agents, and ligands for site-specific targeting such that they selectively reach the desired targets without damaging healthy cells and/or without being blocked by biological barriers. Thus, to increase efficiency per dose of a therapeutic agent, efforts need to be made in the direction of increasing therapeutic agent and imaging agents' delivery, including circumventing the biological barriers that prevent therapeutic agent and imaging agents from reaching their targets.
Of particular interest is the development of delivery systems based on nanotechnology that can achieve both targeting (spatial/distribution control) and controlled release (temporal control) of drugs or therapeutic agents and imaging agents. This is because it is believed that if spatial targeting is combined with temporal controlled release, then an improved therapeutic index may be obtained. For example, if drug release or activation is made locally at the therapeutic site or biophase of interest, then selectivity will be increased by a multiplication of the spatial selectivity with the advantage of local drug release/activation. Further, the therapeutic index may be improved by a combination of spatially selected delivery and a preferable pattern of release for the therapeutic agent over long time periods or using a pulsatile release, which would be preferable for certain pharmacological activities of the therapeutic agents used in, for example, chronotherapeutics. See FIG. 1 for a schematic depiction of the combination of spatial and temporal forms of controlled delivery to achieve a double targeting of drug or therapeutic agent delivery.
Yokoyama et al (Advanced Drug Delivery Reviews, 1996, 21, 77-80) disclose a spatially directed delivery that is achieved with such a carrier system, and has a drug release that is only at a therapeutic site by local heating or cooling. Additionally, Thomas et al (Journal of Controlled Release, 1997, 48, 157-164) disclose a double targeting system that is a thermo-responsive polymeric micelle system. Also, Trail et al (Science 1993, 261, 212-215) disclose selective targeting to tumors and thermo-responsiveness using a polymeric micelle system by introduction of a thermo-responsive polymer segment.